Diarrhea is one of the most common health problems in the world, and even in developed countries is one of the most common infectious diseases. Diarrhea is also one of the most common health problems during childhood. While it has been suggested to administer fermented milk products in the treatment of diarrhea (for example rotavirus associated diarrhea), the medical community continues to seek improved methods or products which would be useful in the prevention of the disease.
In recent years, rotavirus and other enteric viruses have been identified as a major cause of acute diarrhea in infants and young children attending daycare centers. There is an acute need, both domestically and in third world countries, for products and methods that would be effective in preventing infectious diarrhea and diarrhea associated with antibiotic therapy.
Probiotics are a class of microorganisms that are defined as live microbial organisms that beneficially affect the animal and human hosts. The beneficial effects include improvement of the microbial balance of the intestinal microflora or by improving the properties of the indigenous microflora. A better understanding of probiotics in man and animals can be found in the following publications. Fuller R: Probiotics in Man and Animals, J Appl. Bacteriol 1989;66:365-365-378 and Havenaar R, Brink B, Huis In't Veld JHJ: Selection of Strains for Probiotic Use. In Scientific Basis of the Probiotic Use, ed. R. Fuller, Chapman and Hall, London UK, 1992.
The known benefits of enteral administration of probiotic microorganisms include enhanced host defense to disease, improving colonization resistance of the harmful microflora and numerous other areas of health promotion. Probiotics have been suggested to play an important role in the formation or establishment of a well-balanced, indigenous, intestinal microflora in newborn children or adults receiving high doses of antibiotics.
Lactic acid bacteria and specific strains of Lactobacillus have been widely recommended for use as probiotics. See, for example, Gilliland SE: Health and Nutritional Benefits from Lactic Acid Bacteria. Micro Rev. 1990;87;175-188 and Gorbach SL: Lactic Acid Bacteria and Human Health. Annals of Med. 1990;22-37-41. Species of Streptococci, Enterococcus, and Bifidobacteria have also been suggested as being beneficial. One of the more recently studied probiotics is Lactobacillus reuteri. This ubiquitous microorganism resides in the gastrointestinal tract of humans and animals and produces a potent, broad spectrum antimicrobial substance called reuterin. The inhibition of growth of Escherichia, Salmonella, Shigella, Listeria, Campylobacter, Clostridium and species of Staphylococcus by reuterin has been reported. See for example, Axeisson L T, et al (1989), Production of a Broad Spectrum Antimicrobial Substance by Lactobacillus reuteri, Microbial Ecology in Health and Disease 2, 131-136.
Of the intestinal lactic acid bacteria (LAB), L. reuteri is considered a major species. Due to the inability of microbiologists to distinguish L. reuteri from Lactobacillus fermenyum (L. fermetum) in the past, many researchers believe that a large percentage of LAB classified as L. fermentum in older literature, in reality, are strains of L. reuteri.
L. reuteri is a dominant heterofermentative Lactobacillus species residing in the gastrointestinal tract of healthy humans and most animals. Like other lactobacilli, L. reuteri produces acidic metabolic end-products which have considerable antimicrobial activity. It has been recently discovered that metabolism of glycerol by L. reuteri can result in excretion of a metabolic intermediate, 3-hydroxpropionaldehyde, or reuterin. See Axelsson, "Production of a Broad Spectrum Antimicrobial Substance by Lactobacillus reuteri," Microbial Ecology in Health and Disease, 2:131-136, 1989. Reuterin has been shown to have antimicrobial activity against a variety of organisms including Gram-positive and Gram-negative bacteria, yeast, molds and protozoa. See Chung, et al., "In Vitro Studies on Reuterin Synthesis by Lactobacillus reuteri," Microbial Ecology in Health and Disease, 2:137-144, 1989. It is suspected that the antimicrobial activity of reuterin contributes to the survival of L. reuteri within the gastrointestinal ecosystem.
Likewise, L. acidophilus is a normal inhabitant of the human gastrointestinal tract and is a Gram-positive rod widely used in the dairy industry. L. acidophilus is a homofermentative species, fermenting mainly hexose sugar, yielding predominantly lactic acid (85-95%). The use of L. acidophilus predates the 20th century. Bifidobacterium infantis is a Gram-positive, strictly anaerobic, fermentative rod. Bifidobacterium infantis is the predominant form of Bifidobacterium in breast fed infant feces.
Cultures of these organisms are commercially available and are usually supplied as powders. The cultures are alive but in a dormant state which is achieved by a process known as lyophilization (freeze-drying). BioGaia Biologics, Inc. of Raleigh, N.C. promotes and markets a cultured sweet milk and a fermented milk known as BRA milk.TM.. The cultured sweet milk is made by adding to 1% pasteurized and vitaminized low fat milk a Lactobacillus reuteri, Bifidobacterium infantis, Lactobacillus acidophilus culture mixture just before filling cartons. The fermented BRA milk is similar to the cultured sweet milk except that the organisms are allowed to ferment the milk.
The feeding of Bifidobacterium bifidum and Streptococcus thermophilus to infants in hospitals is reported by Savedra, J. et al. in The Lancet, Vol. 344, Oct. 15, 1994. The feeding of these two specific organisms was shown to reduce episodes of diarrhea disease over a control (no organisms). 6.9% of the B. bifidum and S. thermophilus fed infants experienced diarrhea, while 31% of the control group experienced diarrhoeal disease.
U.S. Pat. No. 5,021,245 relates to an infant formula containing a soy polysaccharide fiber source. More specifically, this patent is directed to an infant formula used for the treatment of infantile colic. All of the data and teachings of U.S. Pat. No. 5,021,245 are incorporated herein by reference.
U.S. Pat. No. 5,234,702 relates to a powdered nutritional product which uses a specific antioxidant system to prevent the degradation of the lipid fraction. More specifically, this patent discloses an antioxidant system made up of ascorbyl palmitate, beta carotene and/or mixed tocopherols, and citrate. All of the data and teachings of U.S. Pat. No. 5,234,702 are incorporated herein by reference.
U.S. Pat. No. 5,492,899 discloses an improved enteral nutritional formula containing ribonucleotide equivalents. This patent suggests that such a formula enhances the immune system and alleviates diarrhea. The teachings and data of U.S. Pat. No. 5,492,899 are incorporated herein by reference.
One major aspect that all of the prior art fails to appreciate is the discovery that fermented dairy products, such as yogurts which contain various probiotic agents, present the consuming individual with numerous byproducts that are associated with the fermentation. One aspect of the present invention is the realization that unfermented administration of the probiotic system will be effective in preventing diarrhea. In this regard, pills or capsules containing the probiotic system according to this invention or direct administration of the probiotic powder to the individual is one embodiment of the present invention. Rehydration of the probiotic powder would occur in the patient's stomach and not allow for the fermentation byproducts to form. Thus, the present invention provides an enterally administerable product containing Lacyobacillus reuteri, Lactobacillus acidophilus and Bifidobacterium infantis in an amount which is effective to inhibit diarrhea associated with infectious agents and antibiotic therapy.